Our long-term objective is to understand the mechanisms of angiogenesis in sufficient detail at the cellular, biochemical and molecular level so that this knowledge can be applied clinically to inhibit angiogenesis in tumors as a means of controlling tumor growth and metastasis. Three strategies of angiogenesis inhibition are in various stages of discovery and development: (i) inhibition of capillary blood vessel growth per se (e.g., angiostatic steroids); (ii) inhibition of specific angiogenic molecules in body fluids or on the endothelial cell surface, (e.g., antibodies to FGF); and (iii) inhibition of expression or production of angiogenic factors by tumor cells or other sources. It is now well accepted that tumor growth is angiogenesis-dependent. However, it is not clear when or how angiogenic capability appears, nor what its role is in the development of a tumor. These questions are the subject of this application. A transgenic mouse tumor system will be used in conjunction with a novel in vitro assay to elucidate the biochemical, molecular and genetic mechanisms of the switch to the angiogenic state during the transition from hyperplasia to neoplasia. Additional experiments will test the hypothesis that there is a causal relationship between induction of angiogenesis and tumorigenesis, and thereby establish whether or not neovascularization is a rate-limiting secondary event in tumorigenesis. As part of this aim, transgenic mice will be treated with angiogenesis inhibitors in order to test the efficacy of these drugs for blocking neovascularization and consequently the development of cancers which otherwise inevitably arise. We will examine the generality of angiogenesis in tumorigenesis by characterizing a second tumor progression model in which fibrosarcomas develop in transgenic mice harboring the bovine papilloma virus genome. These studies will be conducted as a collaboration between the laboratories of Judah Folkman and Douglas Hanahan.